Efficacy and Safety Profile of Once-Weekly Dulaglutide in Type 2 Diabetes: a Report on the Emerging New Data

Journal name: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Article Designation: REVIEW Year: 2018 Volume: 11 Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress Running head verso: Kugler and Thiman Running head recto: Update on once-weekly dulaglutide in type 2 diabetes mellitus open access to scientific and medical research DOI: http://dx.doi.org/10.2147/DMSO.S134960

Open Access Full Text Article REVIEW Efficacy and safety profile of once-weekly dulaglutide in type 2 diabetes: a report on the emerging new data

Anne J Kugler1 Abstract: Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist, which has Michael L Thiman2 been on the market in the USA since 2014. Dulaglutide has performed well in head-to-head studies against metformin, glargine, and sitagliptin, where its A1c lowering ranged from 1Department of Pharmacy Practice and Administration, Western -0.78% to –1.64% over 52–104 weeks, and it consistently outperformed each of these agents. University of Health Sciences As an add-on therapy, dulaglutide provided additional A1c lowering of –1.4% to –1.44% College of Pharmacy, Pomona, CA, over monotherapy with glimepiride or glargine at 24 and 28 weeks, respectively. Dulaglutide USA; 2Department of Clinical and Administrative Pharmacy, University outperformed exenatide when added to a regimen of metformin with pioglitazone as well as of Georgia College of Pharmacy, glargine when added to a regimen of metformin with glimepiride. Dulaglutide was shown to Athens, GA, USA be non-inferior to liraglutide when added to metformin. In all AWARD studies other than when

For personal use only. compared to liraglutide, dulaglutide at full strength resulted in significantly more patients achieving their A1c goal. Recent class-wide meta-analyses indicate that the incidence of commonly experienced gastrointestinal (GI) side effects is dose dependent, and nausea and vomiting are less common in longer-acting agents such as dulaglutide, but diarrhea may be more common. Pooled data have shown no increased risk of serious side effects such as pancreatitis or neoplasm with the use of dulaglutide. Given the evidence supporting liraglutide’s cardiovascular benefits, the highly anticipated REWIND trial will have a significant impact on the future place in the therapy of dulaglutide. Keywords: GLP-1 RA, glucagon-like peptide-1 receptor agonist, antidiabetic drugs, diabetes mellitus, injectable, incretin

Introduction Glucagon-like peptide-1 (GLP-1) agonists act at GLP-1 receptors in pancreatic beta cells to increase intracellular cyclic AMP, which in turn increases glucose-dependent insulin secretion; in addition, they act to decrease glucagon release and slow gastric ®

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 emptying. Dulaglutide (Trulicity ; Eli Lilly and Company, Indianapolis, IN, USA) is a long-acting GLP-1 agonist that originally received US Food and Drug Administra- tion (FDA) approval in 2014. The longer half-life of dulaglutide compared to earlier GLP-1 agonists is attributable to alterations that decrease DPP-IV hydrolysis as well as linkage to a constant fragment (F ) that increases protein size and decreases renal Correspondence: Anne J Kugler c 1 Department of Pharmacy Practice and clearance. Administration, Western University of Extensive Phase III study data have been published with regard to dulaglutide, much Health Sciences College of Pharmacy, 309 Second Street, Pomona, CA 91766-1854, of which was part of the AWARD studies, which provide evidence for its use in com- USA bination with several other antidiabetic agents as well as direct comparisons to several Tel +1 909 469 8637 Fax +1 909 469 5539 antidiabetic drug classes. Previously published review articles have provided in-depth Email [email protected] examinations of the earlier AWARD trials.2–5 Since the approval of dulaglutide, several

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follow-up Phase III and Phase IV data have been published Top Injection button providing additional insights into clinical use of this agent. Lock ring The purpose of this article is to review emerging clinical data Indicator pertaining to the efficacy and safety of dulaglutide in type 2 Lock/unlock diabetes mellitus (T2DM).

Literature search strategy A nonsystematic search was conducted on PubMed, Embase, and Cochrane Library using the following search terms:

dulaglutide, LY2189265, Trulicity, glucagon-like peptide-1 Medicine receptor agonists (RAs), or GLP-1 RA. The limits imposed Clear base were English language, human studies, and original research, Bottom/ without any limitation of date range. Articles were filtered needle manually to remove duplicate studies, conference abstracts, end Base cap and studies in patients without T2DM. To ensure complete- Figure 1 Dulaglutide injection device. Note: Reproduced with permission Trulicity (dulaglutide) injection, solution ness, bibliographies of relevant review articles and meta- [instructions for use] Indianapolis, IN: Eli Lilly and Company; 2016. Copyright ©2016 47 analyses were also reviewed. Eli Lilly and Company. All Rights Reserved.

Pharmacokinetics Review of Phase III trial data The maximum plasma concentration of dulaglutide is Within the AWARD study sequence, two trials compared achieved at a median of 48 hours following subcutane- dulaglutide to oral antidiabetic agents, specifically metfor- ous administration, but a period of 2–4 weeks of weekly min (AWARD-3) and sitagliptin (AWARD-5). AWARD-3

For personal use only. medication administration is needed to achieve steady state, was a 52-week study that randomized patients to dulaglutide which is not significantly impacted by the location of injec- (0.75 mg weekly), dulaglutide (1.5 mg weekly), or metformin tion. Dulaglutide is broken down into its component amino (twice daily). Enrolled patients included those with baseline acids by general protein catabolism pathways and is not A1c values of ≥6.5% and ≤9.5% with only lifestyle manage- impacted by the CYP450 isoenzymes or P-glycoprotein. ment or a single, low-dose oral antidiabetic agent. Previous The primary drug interactions of note involve concur- antidiabetic therapy was discontinued during the study lead-in rent use of antidiabetic medications such as insulin or period. Dulaglutide (1.5 mg) demonstrated a significantly sulfonylureas and increased risk of hypoglycemia. Elimi- greater A1c reduction from a baseline of 7.6% compared to nation half-life for both the 0.75 and 1.5 mg weekly doses metformin at 52 weeks, with a significantly greater proportion is about 5 days. No dose adjustment is required for age, of patients achieving A1c values of less than both 6.5% and gender, race, ethnicity, body weight, or renal or hepatic 7% at the study end. No difference in serious adverse events impairment.6 (AEs) was noted, and only constipation was found to occur at a higher rate in the dulaglutide treatment groups compared to Mode of administration metformin. Weight loss was comparable between dulaglutide It is recommended to inject dulaglutide subcutaneously in (1.5 mg) and metformin.8 Details of efficacy parameters in

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 the abdomen, thigh, or upper arm and to rotate the injection AWARD trials are summarized in Table 1, and select safety site. It is available as a single-dose pen containing 0.5 mL end points are detailed in Table 2. AWARD-5 was a 104-week of solution, containing 0.75 or 1.5 mg of active drug and study that randomized patients receiving metformin to either equipped with a locking mechanism to prevent unintentional dulaglutide (0.75 mg weekly), dulaglutide (1.5 mg weekly), or injection (Figure 1). No additional pen needle prescription is sitagliptin (100 mg daily). Patients were eligible for enrollment required, as a needle is already a part of the single-use device. if they were managed with lifestyle modification only and had No shaking or mixing is required, but the solution should be baseline A1c values of >8% and ≤9.5% or were managed on visually inspected for particulate matter and discoloration two or fewer oral antidiabetic agents with baseline A1c values prior to administration.6 A medication guide is required to of ≥7% and ≤9.5%. At study conclusion, both doses of dula- be dispensed with dulaglutide.7 glutide demonstrated significant A1c reduction from baseline

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Table 1 Summary of select efficacy parameters in the AWARD study sequence Study design Study arms Change in A1c A1c<7% A 52-week study of 978 T2DM DUL 1.5 mg QW; DUL 0.75 mg DUL 1.5 mg QW: –1.51±0.06%;a,b DUL DUL 1.5 mg QW: 78%;a,b DUL patients (26-week primary end QW; EXEN 10 mg BID; or 0.75 mg QW: –1.30±0.06%;a,b EXEN 10 mg 0.75 mg QW: 66%;a,b EXEN point; AWARD-1)11 placebo (all received MET + BID: –0.99±0.06%;a placebo: –0.46±0.08% 10 mg BID: 52%;a placebo: 43% pioglitazone) A 78-week study of 810 T2DM DUL 1.5 mg QW; DUL 0.75 mg DUL 1.5 mg QW: –1.08±0.06%;c DUL DUL 1.5 mg QW: 53.2%;e DUL patients (52-week primary end QW; or GLAR daily (all received 0.75 mg QW: –0.76±0.06%;d GLAR daily: 0.75 mg QW: 37.1%; GLAR daily: point; AWARD-2)14 MET + glimepiride) –0.63±0.06% 30.9% A 52-week study of 807 T2DM DUL 1.5 mg QW; DUL 0.75 mg DUL 1.5 mg QW: –0.78±0.06%;f DUL DUL 1.5 mg QW: 62%;g DUL patients (26-week primary end QW; or MET BID 0.75 mg QW: –0.71±0.06%;f MET BID: 0.75 mg QW: 63%;g MET BID: point; AWARD-3)8 –0.56±0.06% 54% A 52-week, open-label study of DUL 1.5 mg QW; DUL 0.75 mg DUL 1.5 mg QW: –1.64%;e,h DUL 0.75 mg DUL 1.5 mg QW: 68%;e DUL 884 T2DM patients QW; or GLAR QHS (all received QW: –1.59%;e,h GLAR QHS: –1.41%h 0.75 mg QW: 69%;e GLAR QHS: (26-week primary end point; insulin lispro) 57% AWARD-4)15 A 104-week study of 1098 DUL 1.5 mg QW; DUL 0.75 mg DUL 1.5 mg QW: –1.10±0.06%;i DUL DUL 1.5 mg QW: 58%;i DUL T2DM patients QW; or SIT 100 mg daily 0.75 mg QW: –0.87±0.06%;i SIT 100 mg 0.75 mg QW: 49%;i SIT 100 mg (52-week primary end point; daily: –0.39±0.06% daily: 33% AWARD-5)9 A 26-week, open-label DUL 1.5 mg QW or LIR 1.8 mg DUL 1.5 mg QW: –1.42±0.05%;j LIR 1.8 mg DUL 1.5 mg QW: 68%; LIR study of 599 T2DM patients daily (all received MET) daily: –1.36±0.05% 1.8 mg daily: 68% (AWARD-6)12 A 24-week study of 300 T2DM DUL 1.5 mg QW or placebo (all DUL 1.5 mg QW: –1.4%;a,h placebo: –0.1%;h DUL 1.5 mg QW: 55.3%;a patients (AWARD-8)18 received glimepiride) placebo: 18.9% A 28-week study of 300 T2DM DUL 1.5 mg QW or placebo (all DUL 1.5 mg QW: –1.44±0.09%;a placebo: DUL 1.5 mg QW: 66.7%;a patients (AWARD-9)17 received GLAR) –0.67±0.09% placebo: 33.3% Notes: aSignificant vs placebo. bSignificant vs exenatide. cSuperior vs glargine. dNon-inferior vs glargine. eSignificant vs glargine. fSuperior vs metformin. gSignificant vs For personal use only. metformin. hStandard error values not reported. iSignificant vs sitagliptin.j Non-inferior vs liraglutide. Abbreviations: AWARD, Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes; BID, twice daily; DUL, dulaglutide; EXEN, exenatide; GLAR, glargine; LIR, liraglutide; MET, metformin; QHS, at bedtime; QW, once weekly; SIT, sitagliptin; T2DM, type 2 diabetes mellitus.

compared to sitagliptin with significantly greater proportions dulaglutide (1.5 or 0.75 mg once weekly), exenatide (10 mg of patients assigned to either dulaglutide dose achieving twice daily), or placebo. Both doses of dulaglutide demonstrated A1c values of <7% and ≤6.5%. Significantly greater weight significantly greater reductions in A1c at 52 weeks compared loss was seen in the dulaglutide 1.5 mg group compared to to exenatide with a significantly greater proportion of patients sitagliptin. A greater incidence of gastrointestinal (GI) AEs achieving A1c values <7% and <6.5% at study conclusion. The was seen in both dulaglutide groups when compared to sita- lower dulaglutide dose demonstrated significantly fewer total GI gliptin.9 Similar significant improvements in glycemic control AEs compared to exenatide while the higher dulaglutide dose were demonstrated in an open-label, nonrandomized study was not significantly different when compared to exenatide.11 conducted in a Japanese patient population that examined the AWARD-6 was a 26-week, open-label, non-inferiority study that addition of dulaglutide (0.75 mg weekly) to single-agent oral randomized patients with A1c values of ≥7% and ≤10% while antidiabetic therapy. For inclusion, patients could be maintained receiving at least 1500 mg of metformin daily to dulaglutide Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 on single-agent therapy with either a sulfonylurea, biguanide, (1.5 mg weekly) or liraglutide (1.8 mg daily). The mean baseline alpha-glucosidase inhibitor, thiazolidinedione, or meglitinide. A1c value in both groups was 8.1%. Dulaglutide was found to A1c reduction from baseline was significant in all groups and be non-inferior to liraglutide with regard to A1c reduction from varied from –1.57% to –1.69%.10 baseline. A greater reduction in body weight was demonstrated Both the AWARD-1 and AWARD-6 studies compared in the liraglutide group compared to dulaglutide. No significant dulaglutide to alternative GLP-1 agonists, exenatide and lira- differences were noted in treatment-emergent AEs.12 An addi- glutide, respectively. AWARD-1 was a 52-week, parallel-arm tional Phase III study in a Japanese patient population lends study that compared multiple doses of dulaglutide to exenatide further data to the comparison of dulaglutide with alternative when added to pioglitazone and metformin background therapy GLP-1 agonists. In patients randomized to either dulaglutide in patients with a mean A1c value of 8.1% at baseline. Patients (0.75 mg weekly) or liraglutide (0.9 mg daily), a significantly were randomized to one of four treatment groups including greater A1c reduction was seen in the dulaglutide arm.13

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Table 2 Summary of select safety parameters in the AWARD study sequence Study Nausea Systolic BP change from HR change from baseline Discontinuation due to AE baseline (mmHg) (bpm) AWARD-111 DUL 1.5 mg QW: 28%;a DUL 1.5 mg QW: 0.11±0.83;a DUL 1.5 mg QW: 2.80±0.52;a,b DUL 1.5 mg QW: 3%; DUL (26-week primary DUL 0.75 mg QW: DUL 0.75 mg QW: DUL 0.75 mg QW: 0.75 mg QW: 1%; EXEN 10 mg end point) 16%;a,b EXEN 10 mg BID: –0.36±0.82;a EXEN 10 mg BID: 2.80±0.51;a,b EXEN 10 mg BID: BID: 3%; placebo: 2% 26%;a placebo: 6% 0.06±0.83;a placebo: 3.40±1.13 1.18±0.52; placebo: 0.61±0.70 AWARD-214 DUL 1.5 mg QW: DUL 1.5 mg QW: 0.17±0.81; DUL 1.5 mg QW: 1.29±0.50;c DUL 1.5 mg QW: 2.9%; DUL (52-week primary 14.3%;c DUL 0.75 mg DUL 0.75 mg QW: 0.09±0.80; DUL 0.75 mg QW: 0.51±0.49; 0.75 mg QW: 2.6%; GLAR daily: end point) QW: 6.6%;c GLAR daily: GLAR daily: 0.51±0.83 GLAR daily: –0.52±0.51 1.5% 1.5% AWARD-38 DUL 1.5 mg QW: 19%; DUL 1.5 mg QW: –1.9±0.89; DUL 1.5 mg QW: 2.4±0.58; DUL 1.5 mg QW: 4.8%; DUL (26-week primary DUL 0.75 mg QW: DUL 0.75 mg QW: –2.6±0.88; DUL 0.75 mg QW: 2.1±0.57; 0.75 mg QW: 2.2%; MET BID: end point) 10.7%; MET BID: 14.6% MET BID: –0.9±0.89 MET BID: 1.6±0.58 3.7% AWARD-415 DUL 1.5 mg QW: 26%;c DUL 1.5 mg QW: –0.26;d DUL DUL 1.5 mg QW: 2.38;c,d DUL DUL 1.5 mg QW: 11%; DUL (26-week primary DUL 0.75 mg QW: 0.75 mg QW: 1.04;d GLAR 0.75 mg QW: 2.27;d GLAR 0.75 mg QW: 8%; GLAR QHS: end point) 18%;c GLAR QHS: 3% QHS: 1.98d QHS: 0.93d 4% AWARD-59 DUL 1.5 mg QW: 17%;e DUL 1.5 mg QW: –0.8±0.7; DUL 1.5 mg QW: 2.4±0.5;e DUL 1.5 mg QW: 11%; DUL (52-week primary DUL 0.75 mg QW: DUL 0.75 mg QW: –0.5±0.7; DUL 0.75 mg QW: 2.1±0.5;e 0.75 mg QW: 8%; SIT 100 mg end point) 13%;e SIT 100 mg daily: SIT 100 mg daily: –0.5±0.7 SIT 100 mg daily: –0.3±0.5 daily: 10% 4% AWARD-612 DUL 1.5 mg QW: 20%; DUL 1.5 mg QW: –3.36±0.7; DUL 1.5 mg QW: 2.37±0.4; DUL 1.5 mg QW: 6%; LIR LIR 1.8 mg daily: 18% LIR 1.8 mg daily: –2.82±0.7 LIR 1.8 mg daily: 3.12±0.4 1.8 mg daily: 6% AWARD-818 DUL 1.5 mg QW: DUL 1.5 mg QW: –0.52±0.96; DUL 1.5 mg QW: 2.92±0.67;a DUL 1.5 mg QW: 4.2%; 10.5%;a placebo: 0% placebo: 0.00±1.54 placebo: 0.30±1.09 placebo: 0% AWARD-917 DUL 1.5 mg QW: –f –f DUL 1.5 mg QW: 4%; placebo: 12.0%;a placebo: 1.3% 1.3% Notes: aSignificant vs placebo.b Significant vs exenatide.c Significant vs glargine.d SD/standard error not reported. eSignificant vs sitagliptin.f Not evaluated. For personal use only. Abbreviations: AE, adverse event; AWARD, Assessment of Weekly AdministRation of LY2189265 (dulaglutide) in Diabetes; BID, twice daily; BP, blood pressure; DUL, dulaglutide; EXEN, exenatide; GLAR, glargine; HR, heart rate; LIR, liraglutide; MET, metformin; QHS, at bedtime; QW, once weekly; SIT, sitagliptin.

Several AWARD studies have compared dulaglutide to AEs were comparable across treatment groups.14 AWARD-4 basal insulin, specifically insulin glargine. The AWARD-2 was a 52-week, open-label, non-inferiority trial that enrolled study was a 78-week, open-label, non-inferiority trial that patients with A1c values of ≥7% and ≤11% while receiving included patients with A1c values of ≥7% and ≤11% while 1–2 doses of insulin per day. Participants were randomized maintained on one to three oral antidiabetic medications. to treatment with dulaglutide (0.75 mg weekly), dulaglutide Patients were randomized to treatment with dulaglutide (1.5 mg weekly), or insulin glargine, with all patients receiv- (0.75 mg weekly), dulaglutide (1.5 mg weekly), or insulin ing insulin lispro. Patients were permitted to be maintained glargine, and all patients received metformin and glimepiride on metformin during the study; however, no other oral background therapy. Insulin glargine was adjusted using a agents were allowed. Dulaglutide (both 0.75 and 1.5 mg) standardized titration algorithm. A1c reduction with dula- demonstrated significantly greater A1c reduction compared glutide (0.75 mg) was found to be non-inferior to insulin to insulin glargine, although it is noteworthy that significantly

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 glargine, and dulaglutide (1.5 mg) was found to be superior greater doses of insulin lispro were utilized in both dula- to insulin glargine at week 52. A significantly greater pro- glutide treatment groups. At study conclusion, dulaglutide portion of patients receiving dulaglutide (1.5 mg) achieved (1.5 mg) resulted in a greater proportion of patients achiev- an A1c value of <7.0% at week 52 compared to insulin ing an A1c value of <7% compared to insulin glargine, and glargine, while both dulaglutide doses demonstrated a sig- there were no differences between treatment groups in the nificantly greater proportion of patients achieving an A1c proportion of patients achieving an A1c value of ≤6.5%. value of ≤6.5% at the same time point. Both dulaglutide Fewer serious AEs occurred in the dulaglutide 1.5 mg group doses were associated with weight loss, while insulin glargine compared to insulin glargine, but GI AEs were more likely demonstrated weight gain; this difference was found to be in both dulaglutide groups compared to insulin glargine.15 significant. GI AEs were more common in both dulaglutide These results are further supported by an additional Phase groups when compared to insulin glargine; however, serious III study conducted in a Japanese patient population com-

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paring dulaglutide to insulin glargine in patients maintained between groups; however, a greater incidence in GI AEs was on sulfonylurea and/or biguanide. In this patient population, noted in the dulaglutide group compared to placebo. Both dulaglutide demonstrated a significantly greater A1c reduc- total hypoglycemia and symptomatic hypoglycemia were tion compared to insulin glargine.16 significantly more frequent in those receiving dulaglutide, A recently published study (AWARD-9) provides addi- p<0.05.18 tional data for the use of dulaglutide in combination with insulin therapy in patients with T2DM. AWARD-9 was a Cardiovascular (CV) impact 28-week, parallel-arm study that randomized patients receiv- A comprehensive meta-analysis of GLP-1 RAs was con- ing titrated insulin glargine to either dulaglutide (1.5 mg ducted to investigate the potential impact of these agents weekly) or placebo. Patients with A1c values of ≥7% and on mortality and CV events. A total of 113 trials were ≤10.5% who were maintained on a stable dose of insulin included, which used exenatide, liraglutide, lixisenatide, glargine were eligible for enrollment. In addition, patients albiglutide, dulaglutide, and semaglutide as investiga- could be maintained on metformin therapy; however, this tional arms. The risk of all-cause mortality and risk of CV was not a requirement for inclusion. At baseline, patients’ mortality were lower in patients treated with a GLP-1 RA average age was ~60 years, study groups were 56.7%–58.7% (p=0.015 and p=0.009, respectively). No statistical differ- male, average body mass index (BMI) was ~33 kg/m2, and ence was seen for the end points of myocardial infarction an average A1c value was 8.3%–8.4%. A significantly larger (MI), heart failure, or stroke. Four dulaglutide studies were reduction in A1c was seen with dulaglutide (–1.44%) com- included, which showed a lower risk of all-cause mortal- pared to placebo (–0.67%), p<0.001. More than 66% of dula- ity (p=0.044), but not a significantly reduced risk of CV glutide patients achieved an A1c value of <7.0% compared to mortality. Dulaglutide was the only once-weekly agent to 33.3% of placebo patients, p<0.001, and 50% of dulaglutide show this benefit individually.19 In a meta-analysis of nine patients reached an A1c value of ≤6.5% compared to 16.7% randomized, Phase II and III dulaglutide trials, the data of patients assigned to placebo, p<0.001. Dulaglutide dem- of 6010 subjects were pooled, 3885 of whom received For personal use only. onstrated a significant reduction in weight from baseline dulaglutide. A blinded adjudication committee was used (–1.91 kg) and resulted in a –2.41 kg difference compared to to independently make determinations regarding reported placebo, p<0.001. A greater number of treatment-emergent events during the treatment period of each study and up AEs were seen in the dulaglutide treatment group compared to 30 days following discontinuation of treatment drugs. to placebo, with a significantly greater incidence of GI AEs The primary composite end point included death due to and decreased appetite. A significant difference in serious CV cause, nonfatal MI, nonfatal stroke, or hospitalization AEs was not demonstrated.17 for unstable angina and resulted in a hazard ratio of 0.57 An additional, more recently published study (AWARD-8) for patients receiving dulaglutide compared to placebo or evaluated the impact of adding dulaglutide to background active comparator (p=0.046), but no difference when the sulfonylurea therapy. This was a 24-week, parallel-arm events were examined separately.20 These data are encour- study that randomized patients maintained on glimepiride aging, as they support the use of dulaglutide in T2DM to dulaglutide (1.5 mg weekly) or placebo. Patients with without the concern of increased CV risk, at least in the A1c values of ≥7.5% and ≤9.5% maintained on a consistent short term. The impact of the long-term use of dulaglutide sulfonylurea dose were eligible for enrollment. At baseline, on the risk of major CV events is currently being examined

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 patients’ average age was ~58 years, study groups were in the ongoing Researching Cardiovascular Events with a 53.3%–56.5% female, average BMI was 30.9–32.4 kg/m2, Weekly INcretin in Diabetes (REWIND) trial.21 Final data and average A1c value was 8.4%. Dulaglutide demonstrated collection is estimated to be completed by July 2018, and a significantly greater reduction in A1c compared to placebo patients will be followed for an average of 6.5 years. resulting in a -1.3% treatment difference, p<0.001. By Many GLP-1 RAs agents have been shown to impact the study end, a greater proportion of dulaglutide patients patient blood pressure (BP) and heart rate (HR).22 To examine achieved A1c values of <7% and ≤6.5%, 55.3%, and 40%, the potential impact of dulaglutide on these vital signs, 755 respectively, compared to placebo patients, 18.9% and 9.4%, patients were provided with ambulatory BP monitors and respectively, p<0.001 for both comparisons. There was no sig- were randomized to dulaglutide at either strength or placebo nificant difference in body weight change between groups at for 26 weeks. Patients were 56 years old on average, were study conclusion. Treatment-emergent AEs were comparable taking at least one oral medication for the treatment of dia-

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betes, and had an average A1c value of 7.9%. Dulaglutide placebo, metformin, and liraglutide overall (7.8% vs 10.6%; (0.75 mg) was non-inferior to placebo in change to 24-hour relative risk [RR] 1.07; 95% CI 0.80–1.44). When dulaglutide BP and HR, while dulaglutide (1.5 mg) showed a statisti- monotherapy was compared to placebo alone, the RR was 2.58 cally significant decrease in systolic BP of 2–3 mmHg and (95% CI 1.05–6.31), but there was no significant difference a statistically significant increase in HR of 3–4 bpm.23 detected when compared to metformin or liraglutide individually. A similar pattern was seen when dulaglutide was used as Special populations add-on therapy and compared to placebo, sitagliptin, exenatide, A post hoc examination of subjects from AWARD 1–6 trials liraglutide, and glargine (24.5% vs 24.5%; RR 1.07; 95% CI was conducted to explore the efficacy and safety of the use of 0.89–1.30). When add-on dulaglutide was compared to placebo dulaglutide in Hispanic/Latino patients. Of the studies included, alone, the RR of hypoglycemia was again increased (RR 1.82; 3136 subjects received dulaglutide and 949 of those subjects 95% CI 1.44–2.31), but as with monotherapy, there was no self-identified as having Hispanic/Latino ethnicity. Baseline difference when compared to metformin. A difference was seen characteristics for subjects of Hispanic/Latino ethnicity were compared to sitagliptin 100 mg daily with the 1.5 mg weekly similar to the population at large, except that there were more dose of dulaglutide added on (RR 2.14; CI 1.18–3.89), but not female patients and the average weight was slightly lower. The the 0.75 mg dose. The risk of hypoglycemia was also greater percentage of Hispanic/Latino patients who achieved A1c goals, with dulaglutide add-on when compared to glargine (weighted percent reduction in A1c, weight change, and AEs, including mean difference [WMD] 0.69; 95% CI 0.56–0.85).27 When hypoglycemia, were similar to the overall population.24 data were pooled from three Phase III studies in Japan, older Post hoc analysis of subjects who received dulaglutide patients, patients with longer-standing diabetes (≥7 years), in three, non-AWARD, Phase III trials conducted in Japan lower baseline body weight, and subjects with concurrent use showed similar efficacy at 26 weeks in 855 subjects, regard- of biguanide were all found to be more likely to experience less of age or BMI. Elderly patients (>65 years) with a BMI hypoglycemia, but concurrent use of sulfonylurea (SU) was the of <25 kg/m2, however, were more likely to experience side most significant association with hypoglycemia.28 In a network For personal use only. effects overall than younger patients or elderly patients with meta-analysis including 30 unique studies involving once- a BMI of ≥25 kg/m2, with statistically significant differences weekly GLP-1 RAs, nine of which were dulaglutide studies, in the incidences of constipation and decrease in appetite. there were no significant differences found in the frequency Subjects were predominantly male (76%), had an average of documented or symptomatic hypoglycemia among once- A1c value at baseline of 8.3%, and all were Japanese, mak- weekly GLP-1 RAs.29 ing generalizability of these results limited.25 When gender differences were explored in a separate analysis of two of the Acute pancreatitis abovementioned Phase III studies, efficacy of dulaglutide was Data from four Phase II trials and the first five AWARD trials found to be similar, but greater weight loss (or less weight gain) were pooled to assess the risk of acute pancreatitis in patients was seen in female subjects, despite having a lower baseline treated with dulaglutide. Phase II trials ranged from 12 to body weight than male subjects. Females receiving dulaglutide 26 weeks in length, using doses of 0.1–3.0 mg, and Phase monotherapy lost an average of 1.32 kg, whereas males gained III trials ranged from 52 to 104 weeks, using only doses of 0.09 kg. When used in combination with a sulfonylurea and/or 0.75 and 1.5 mg. A total of 6005 subjects were examined, biguanide, female patients lost an average of 1.13 kg, whereas 4006 of whom received dulaglutide. Comparator therapies

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 males lost 0.21 kg. Females experienced more AEs overall than included placebo, metformin, sitagliptin, exenatide, and males, and specifically experienced more nausea, constipa- insulin glargine. The resulting exposure-adjusted incidence tion, and diarrhea, but there was no difference in incidences rates of acute pancreatitis were 0.85 patients/1000 patient- of hypoglycemia between genders. Females comprised 23% years for dulaglutide, 3.52 patients/1000 patient-years for of the study population (total n=778).26 placebo, 4.71 patients/1000 patient-years for sitagliptin, and there were no events of pancreatitis in exenatide, metformin, Additional safety data or glargine groups. This study was limited by sample size, Hypoglycemia short duration of exposure to the study drug, and exclusion of In a meta-analysis of 12 Phase II and Phase III, randomized, patients with prior history of pancreatitis, but reflects a lower controlled trials, dulaglutide showed a similar incidence risk of acute pancreatitis in dulaglutide-treated individuals of hypoglycemia when used as monotherapy compared to when compared to those receiving placebo.30

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Dovepress Update on once-weekly dulaglutide in type 2 diabetes mellitus

The data from three Phase III trials were pooled to evaluate involving GLP-1 RAs showed that nausea and diarrhea were the risk of acute pancreatitis in the Japanese population when both dose-dependent side effects when subjects were treated treated with dulaglutide (0.75 mg). Out of 917 patients who with GLP-1 RAs, including dulaglutide. The incidence of received dulaglutide, one occurrence of acute pancreatitis nausea and vomiting was significantly increased in subjects was determined to be drug induced, resulting in an exposure- taking a GLP-1 RA with metformin (p=0.04 and p=0.0009, adjusted incidence rate of 2.651 patients/1000 patient-years. respectively). Long-acting agents (albiglutide, dulaglutide, Elevations of amylase (>1× upper limit of normal [ULN] exenatide weekly, and liraglutide) generally caused less nau- and ≥3× ULN) and lipase (≥3× ULN) were similar in the sea (p<0.0001) and vomiting (p=0.013), but more diarrhea dulaglutide arms compared to liraglutide, insulin glargine, (p=0.0013) than short-acting agents (exenatide twice daily and placebo arms; however, lipase elevations >1× ULN were and lixisenatide) when given at the highest available dose. significantly higher in the dulaglutide and liraglutide arms When compared to liraglutide daily, dulaglutide had similar than in the insulin glargine and placebo arms. This analysis RR of nausea (p=0.74) and vomiting (p=0.65) and a lower shares the same limitations as the previous pooled study, but is RR of diarrhea (p=0.015). Albiglutide showed a lower RR even smaller and has a maximum study duration of 52 weeks.31 for all the three, while exenatide weekly showed a lower risk of only nausea when compared to liraglutide.33 Neoplasms The aforementioned network meta-analysis examining A total of 26 trials involving once-weekly GLP-1 RAs were once-weekly GLP-1 RAs also calculated odds ratio (OR) for examined in a meta-analysis to determine whether there was the AE of nausea with use of each agent when compared to an increased risk of developing tumors of any kind with the placebo. Dulaglutide (1.5 and 0.75 mg) showed moderate use of dulaglutide, exenatide-ER (extended release), or albi- ORs (4.35 and 2.44, respectively), with less nausea occur- glutide. The results indicated that there was not an increased ring with use of albiglutide (OR=1.3) and once weekly risk of tumor development in any tissues with the use of these exenitide (OR=2.38), but more nausea with use of taspoglu- three agents, regardless of which agent was selected or the tide (OR=6.19 for 10 mg strength and OR=8.32 for 20 mg For personal use only. duration of therapy.32 strength).29 In a pooled analysis of three Phase III studies conducted in Japan, female patients, patients with longer- Comparison to other GLP-1 standing diabetes, lower baseline body weight, and those using RAs agents concurrent SUs were all more likely to experience nausea.28 Efficacy Although there are no head-to-head trials between dulaglutide Microvascular complications and other once-weekly agents, a network meta-analysis includ- A meta-analysis was conducted to investigate the incidence of ing 34 unique studies involving once-weekly GLP-1 RAs was nephropathy (defined as chronic renal failure, doubling of serum conducted. Out of 34 studies, 10 included dulaglutide; addi- creatinine (SCr), need for continuous renal replacement therapy, tional agents examined include exenatide weekly, taspoglutide, or macroalbuminuria) and retinopathy (defined as any AE and albiglutide. Dulaglutide (1.5 mg weekly) was found to have reported as “retinopathy,” retinal photocoagulation, treatment the largest mean A1c reduction compared to placebo (–1.4%). with intravitreal agents, macular edema, vitreous hemorrhage, Reduction in fasting plasma glucose (FPG) levels was highest retinal detachment, or the onset of diabetes-related blindness) with the use of exenatide weekly (–2.2 mmol/L [CI –2.6 to in subjects receiving a GLP-1 RA. Investigators found that,

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 –1.8 mmol/L]/-39.6 mg/dL [CI –46.8 to –32.4 mg/dL] reduc- as a class, there was no increased or decreased risk overall for tion), followed closely by dulaglutide (1.5 mg), which showed a either retinopathy or nephropathy; however, semaglutide was –2.2 mmol/L (CI –2.6 to –1.7 mmol/L)/–39.6 mg/dL (CI –46.8 associated with a lower OR for nephropathy, and a higher OR to –30.6 mg/dL) reduction. Weight reduction was largest with for retinopathy (based on only one study). Liraglutide was the use of taspoglutide (20 mg; –1.3 kg; CI –1.9 to –0.7 kg), fol- associated with a lower risk of retinopathy, while dulaglutide lowed by weekly exenatide and dulaglutide (1.5 mg; –0.8 kg; CI reflected no increased or decreased risk for either microvas- –1.5 to –0.1 kg and –0.8 kg; CI –1.4 to –0.1 kg, respectively).29 cular complication.34 A subsequent publication investigating renal outcomes in participants of the LEADER trial found that GI side effects there were fewer instances of new-onset macroalbuminuria in A systematic meta-analysis examining the incidence of subjects in the liraglutide arm compared to placebo (hazard nausea, vomiting, and diarrhea in published Phase III trials ratio 0.74; p=0.0004) after a median follow-up of 3.84 years.

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The same study also showed a decreased occurrence of the Patient perspective composite renal outcome (which consisted of new-onset, Treatment satisfaction over 52 weeks was examined in persistent macroalbuminuria, persistent doubling of the SCr subjects from the AWARD-1 and AWARD-3 trials using the and an estimated glomerular filtration rate [eGFR]≤45 mL/ Diabetes Treatment Satisfaction Questionnaire, status ver- min/1.73 m2, need for continuous renal replacement therapy sion (DTSQs) and change version (DTSQc). DTSQs scores with no reversible cause of renal disease, or death from renal were significantly improved at 26 weeks in subjects given disease) in the liraglutide arm (hazard ratio 0.78; p=0.003).35 dulaglutide (at either strength) when compared to placebo or exenatide, a pattern which persisted at 52 weeks when Prediction of therapeutic response dulaglutide was compared to exenatide. Subjects on exenatide Post hoc analysis of the AWARD-1 and AWARD-5 trial data reported lesser improvement in perceived hyperglycemia for patients in the dulaglutide arms showed a strong associa- compared to subjects receiving dulaglutide, as well as an tion between lower fasting blood glucose (FBG) levels at week increase in perceived frequency of hypoglycemia at 26 and 2 (<142.2 mg/dL or <7.9 mmol/L) and glycemic response at 52 weeks. There were no significant differences in DTSQs week 26, which was significant for both strengths of dulaglu- scores between dulaglutide arms and the metformin arm tide. Glycemic response was defined as either 1) achievement in AWARD-3, but dulaglutide patients showed a greater of A1c <7%, 2) A1c reduction of >0.8% if baseline was <8%, improvement in perceived hyperglycemia at 52 weeks.38 3) A1c reduction of >1.1% if baseline was ≥8% and <9%, or Additional patient-reported outcome (PRO) question- 4) A1c reduction >1.6% if baseline was ≥9%.36 This may allow naires were used in other AWARD trials. The Ability to for the use of FBG values at week 2 as a predictor of future Perform Physical Activities of Daily Living (APPADL) and therapy response, although data did not show an association Impact of Weight on Self-Perception (IW-SP) were adminis- between high FBG at week 2 and therapy failure. tered to AWARD-1, AWARD-2, AWARD-3, AWARD-4, and Data from the first six AWARD trials were pooled to AWARD-6 subjects. Dulaglutide arms showed no significant examine baseline characteristics for potential predictors of

For personal use only. difference in the APPADL scores when compared to metfor- therapeutic response to dulaglutide treatment at week 26. min, exenatide, or liraglutide at 26 weeks, which persisted The primary factor associated with a greater reduction in at week 52 for metformin and exenatide comparators. When A1c (-0.594% additional; p<0.0001) in the 2806 patients compared to insulin glargine, results were conflicting. studied was higher baseline A1c. To a much lesser extent, AWARD-2 showed a significantly higher APPADL score for associations were seen between the age group of ≤65 years, both strengths of dulaglutide compared to glargine at week fasting serum insulin of ≤55 pmol/L (≤7.92 mIU/L) or eGFR 52, but at 78 weeks, this difference only persisted for the of ≤100 mL/min/1.73 m2, and additional A1c lowering of 1.5 mg dose. In AWARD-4, however, no significant differ- -0.175 (p=0.003), -0.197 (p<0.0001), and -0.143 (p=0.002), ences in APPADL scores were seen with either strength of respectively. Subjects with lower fasting serum glucose (FSG) dulaglutide when compared to glargine use at 26 or 52 weeks. exhibited less A1c lowering (+0.0468; p<0.0001) than those IW-SP scores were significantly higher in the dulaglutide with higher FSG values at baseline.37 When data were pooled 1.5 mg group compared to insulin glargine in AWARD-4 (at from the three Phase III trials conducted in Japan, a similar 26 and 52 weeks) and AWARD-2 (at 78 weeks), but there associate was seen between higher A1c and greater response was no difference when compared to metformin, exenatide, to dulaglutide in A1c lowering; however, subjects with a lower or liraglutide. The Impact of Weight on Quality of Life-Lite

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 baseline body weight (<70 kg), lower BMI (<25 kg/m2), and (IWQOL-Lite) was administered to AWARD-5 subjects only higher age (≥65 years) were also likely to experience greater and showed a significantly higher scoring in the dulaglutide A1c lowering. Patients with a lower baseline A1c were more 1.5 mg group compared to sitagliptin at 104 weeks. The likely to achieve an A1c goal of <7%. Female subjects, those Adult Low Blood Sugar Survey (ALBSS) was administered with lower body weight, higher A1c, and concurrent biguanide to AWARD-2 and AWARD-4 subjects, but no difference therapy tended to lose more weight on dulaglutide.28 These was seen in scores in AWARD-4, while AWARD-2 showed a results suggest that patients in the general population with significantly larger improvement in score in both dulaglutide poorly controlled T2DM are likely to achieve greater A1c groups at weeks 52 and 78, including the separate worry and lowering than those who are closer to their glycemic goals, and behavior components.39 that some Japanese patients may have additional factors that Patients from two other Phase III trials were given the Percep- are associated with a stronger response to dulaglutide therapy. tions about Medications-Diabetes 21 Questionnaire – Japanese

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Dovepress Update on once-weekly dulaglutide in type 2 diabetes mellitus

version (PAM-D21-J) and the Injectable Diabetes Medication benefits for patients with a history atherosclerotic CV disease.41 Questionnaire – Japanese version (IDMQ-J) at week 26 in each At this time, the only GLP-1 agonist to carry an FDA indication study. Patients in these studies were exclusively Japanese and for the reduction in the risk of major CV events is liraglutide. >70% were male, with an average age of 57 years and an A1c This is based on results of the LEADER trial, which demon- value of 8%. Scores for dulaglutide (0.75 mg weekly) in the strated a hazard ratio of 0.87; 95% CI 0.78–0.97, p<0.01, for area of perceived convenience and flexibility were significantly superiority for the primary outcome of first occurrence of death higher than liraglutide (0.9 mg daily), insulin glargine (daily), from CV causes, nonfatal MI, or nonfatal stroke.42 The newly or placebo; scores for perceived effectiveness and emotional approved GLP-1 agonist, semaglutide, also demonstrated a sig- effects were also higher for dulaglutide than glargine or placebo, nificant reduction at the primary outcome of the first occurrence with no statistically significant difference in perceived physical of CV death, nonfatal MI, or nonfatal stroke in SUSTAIN-6. effects. Higher satisfaction was reported by dulaglutide subjects This was driven by a reduction in the incidence of nonfatal compared to all other therapies studied. Dulaglutide also scored stroke, which was the only outcome to demonstrate a significant higher than placebo in ease of use, lifestyle impact, and blood reduction when analyzed separately. It is, however, notable that glucose control and higher than glargine in blood glucose SUSTAIN-6 was designed as a non-inferiority trial without a control. PRO questionnaires were considered exploratory in prespecified superiority analysis, and the median follow-up this evaluation, as neither were psychometrically validated.40 It was 2.1 years, representing a relatively short study duration.43 is likely that the better performance overall of dulaglutide on The recently published EXSCEL trial evaluated the CV out- both PROs is driven by its once-weekly administration; however, comes of treatment with once-weekly exenatide and found no patients on placebo injections were only required to administer significant difference in major CV events when compared to weekly and yet dulaglutide still consistently outperformed placebo.44 Outside of the class of GLP-1 agonists, separate placebo with both tools. Of note, PRO studies used prefilled studies examining the use of empagliflozin and canagliflozin syringes to administer dulaglutide, rather than the commercially in patients with T2DM and high CV risk showed a reduction available single-use pen, which would likely improve ease of in the composite end point of death from CV cause, nonfatal For personal use only. use even further. MI, and nonfatal stroke compared to placebo.45,46 While some evidence has supported a reduction in overall mortality with Discussion dulaglutide, the currently available data have not demonstrated Phase III studies have demonstrated comparable or supe- an advantage associated with dulaglutide in terms of CV out- rior efficacy of dulaglutide to several therapeutic options comes.19 The findings of the ongoing REWIND trial will further in T2DM. As a result, dulaglutide presents a reasonable define the impact of dulaglutide on CV outcomes, as well as therapeutic selection for the escalation of therapy in patients provide insights into whether reduction in CV outcomes may maintained on oral therapy as well as those already initiated be a class effect of GLP-1 agonists. on basal insulin. In comparison to alternative GLP-1 ago- Overall, data have demonstrated acceptable tolerability nists, dulaglutide has demonstrated superior A1c reduction and safety of dulaglutide. Rates of hypoglycemia do not vs liraglutide and exenatide. Multiple Phase III studies have appear to differ significantly from other once-weekly GLP-1 shown the effectiveness of dulaglutide as second- or third- agonists.29 Pooled data have not demonstrated a significant line therapy in addition to oral hypoglycemic agents, which increase in the risk of pancreatitis compared to placebo; supports current guideline recommendations for place in however, the available literature has a number of limita-

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 therapy of GLP-1 agonists.41 There are additional Phase III tions.30 Likewise, compiled data to date have not supported data that support the efficacy of dulaglutide when added to an increased risk of neoplasm with the use of dulaglutide.32 basal insulin, specifically in comparison to placebo; therefore, GI AEs present a commonly encountered reason for the dis- further study vs an active comparator in the role of escala- continuation of GLP-1 agonists. Long-acting GLP-1 agonists, tion of injectable therapy would provide useful insights into excluding taspoglutide, have demonstrated less nausea and appropriate patient selection. Regardless, current evidence vomiting than short-acting GLP-1 agonists.33 In comparison does establish dulaglutide as a reasonable therapeutic option to other long-acting agents, dulaglutide has demonstrated a in addition to basal insulin. similar risk of nausea compared to liraglutide, but a greater The 2018 American Diabetes Association (ADA) Standards risk of nausea compared to albiglutide and once-weekly of Medical Care in diabetes have placed particular focus on the exenatide.29,33 The available data do not establish an impact initiation of second-line hypoglycemic agents with proven CV of dulaglutide on microvascular complications.34

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Patient-specific factors that may alter the impact of dula- 8. Umpierrez G, Tofe Povedano S, Perez Manghi F, Shurzinske L, Pechtner glutide include female gender (greater weight loss, higher risk V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes of AEs) and elderly patients (>65 years) with normal BMI Care. 2014;37(8):2168–2176. (higher risk of experiencing side effects).25,26 These patterns, 9. Weinstock RS, Guerci B, Umpierrez G, Nauck MA, Skrivanek Z, Milicevic Z. Safety and efficacy of once-weekly dulaglutide versus sitagliptin after however, were seen during ad hoc analyses of studies includ- 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a ing only Japanese patients, requiring additional investigation randomized, phase III study. Diabetes Obes Metab. 2015;17(9):849–858. to determine whether they exist in other populations. In the 10 Emoto M, Terauchi Y, Ozeki A, Oura T, Takeuchi M, Imaoka T. A 1-year safety study of dulaglutide in Japanese patients with type 2 diabetes on broader population, higher A1c upon initiation and lower a single oral hypoglycemic agent: an open-label, nonrandomized, phase FBG values after 2 weeks of therapy may be useful predictors 3 trial. Endocr J. 2015;62(12):1101–1114. 11. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglu- 37 of therapeutic response to dulaglutide. tide added onto pioglitazone and metformin versus exenatide in type 2 In terms of the assessment of patient perspective, PRO diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. questionnaires overall indicate that patient perceptions of 2014;37(8):2159–2167. 12. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide various quality of life markers with the use of dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 are, at a minimum, equivalent to mainstays of therapy, and diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349–1357. in some instances, there is a perceived improvement with 13. Odawara M, Miyagawa J, Iwamoto N, Takita Y, Imaoka T, Takamura dulaglutide use.38–40 T. Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide significantly decreases glycated haemoglobin compared with once- daily liraglutide in Japanese patients with type 2 diabetes: 52 weeks Conclusion of treatment in a randomized phase III study. Diabetes Obes Metab. Dulaglutide represents a well-tolerated and efficacious 2016;18(3):249–257. 14. Giorgino F, Benroubi M, Sun JH, Zimmermann AG, Pechtner V. Effi- option in the treatment of T2DM. Ongoing trial data will cacy and safety of once-weekly dulaglutide versus insulin glargine in better inform the future place in the therapy of dulaglutide patients with type 2 diabetes on metformin and glimepiride (AWARD-2). considering the recent guideline emphasis on agents with Diabetes Care. 2015;38(12):2241–2249. 15. Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus bed- beneficial effects on CV outcomes. time insulin glargine, both in combination with prandial insulin lispro, For personal use only. in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet. 2015;385(9982):2057–2066. Acknowledgment 16. Araki E, Inagaki N, Tanizawa Y, Oura T, Takeuchi M, Imaoka T. Efficacy The authors would like to acknowledge Palak Desai, Van and safety of once-weekly dulaglutide in combination with sulphonyl- Kieu, Kelli Shiroma, and Vincent Mach, PharmD candidates urea and/or biguanide compared with once-daily insulin glargine in Japanese patients with type 2 diabetes: a randomized, open-label, phase 2018, for their role in drafting article summaries. III, non-inferiority study. Diabetes Obes Metab. 2015;17(10):994–1002. 17. Pozzilli P, Norwood P, Jodar E, et al. Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor Disclosure agonist dulaglutide to titrated daily insulin glargine in patients with type The authors report no conflicts of interest in this work. 2 diabetes (AWARD-9). Diabetes Obes Metab. 2017;19(7):1024–1031. 18. Dungan KM, Weitgasser R, Perez Manghi F, et al. A 24-week study to evaluate the efficacy and safety of once-weekly dulaglutide added on References to glimepiride in type 2 diabetes (AWARD-8). Diabetes Obes Metab. 1. Barrington P, Chien JY, Showalter HDH, et al. A 5-week study of the 2016;18(5):475–482. pharmacokinetics and pharmacodynamics of LY2189265, a novel, 19. Monami M, Zannoni S, Pala L, et al. Effects of glucagon-like peptide-1 long-acting glucagon-like peptide-1 analogue, in patients with type 2 receptor agonists on mortality and cardiovascular events: a compre- diabetes. Diabetes Obes Metab. 2011;13(5):426–433. hensive meta-analysis of randomized controlled trials. Int J Cardiol. 2. Gurung T, Shyangdan DS, O’Hare JP, Waugh N. A novel, long-acting 2017;240:414–421. glucagon-like peptide receptor-agonist: dulaglutide. Diabetes Metab 20. Ferdinand KC, Botros FT, Atisso CM, Sager PT. Cardiovascular safety

Diabetes, Metabolic Syndrome and Obesity: Targets Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 29-Dec-2018 Syndr Obes. 2015;8:363–386. for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta- 3. Jendle J, Grunberger G, Blevins T, Giorgino F, Hietpas RT, Botros FT. analysis of prospectively adjudicated cardiovascular events. Cardiovasc Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: Diabetol. 2016;15(1):38. a comprehensive review of the dulaglutide clinical data focusing on 21. Eli Lilly and Company. Researching cardiovascular events with a weekly the AWARD phase 3 clinical trial program. Diabetes Metab Res Rev. incretin in diabetes (REWIND). Bethesda, MD: National Library of 2016;32(8):776–790. Medicine; 2011–2013. Available from: clinicaltrials.gov. NLM Identi- 4. Thompson AM, Trujillo JM. Advances in the treatment of type fier: NCT01394952. Accessed March 22, 2018. 2 diabetes: impact of dulaglutide. Diabetes Metab Syndr Obes. 22. Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor agonists on blood 2016;9:125–136. pressure, heart rate and hypertension among patients with type 2 dia- 5. Scheen AJ. Dulaglutide for the treatment of type 2 diabetes. Expert betes: a systematic review and network meta-analysis. Diabetes Res Opin Biol Ther. 2017;17(4):485–496. Clin Pract. 2015;110(1):26–37. 6. Trulicity (dulaglutide) injection, solution [prescribing information] 23. Ferdinand KC, White WB, Calhoun DA, et al. Effects of the once-weekly Indianapolis, IN: Eli Lilly and Company; 2017. glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory 7. Trulicity (dulaglutide) injection, solution [medication guide] Indianapo- blood pressure and heart rate in patients with type 2 diabetes mellitus. lis, IN: Eli Lilly and Company; 2017. Hypertension. 2014;64(4):731–737.

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Dovepress Update on once-weekly dulaglutide in type 2 diabetes mellitus

24. Davidson JA, Manghi FP, Yu M, Linetzky B, Lando LF. Efficacy and 35. Mann JFE, Orsted DD, Buse JB. Liraglutide and renal outcomes in type safety of dulaglutide in Hispanic/Latino patients with type 2 diabetes in 2 diabetes. N Engl J Med. 2017;377(22):2197–2198. the AWARD clinical program. Endocr Pract. 2016;22(12):1406–1414. 36. Grunberger G, Forst T, Fernandez Lando L, et al. Early fasting glucose 25. Hamano K, Nishiyama H, Matsui A, Sato M, Takeuchi M. Efficacy and measurements can predict later glycaemic response to once weekly safety analyses across 4 subgroups combining low and high age and dulaglutide. Diabet Med. 2016;33(3):391–394. body mass index groups in Japanese phase 3 studies of dulaglutide 0.75 37. Wysham C, Guerci B, D’Alessio D, Jia N, Botros FT. Baseline factors asso- mg after 26 weeks of treatment. Endocr J. 2017;64(4):449–456. ciated with glycaemic response to treatment with once-weekly dulaglu- 26. Onishi Y, Oura T, Matsui A, Matsuura J, Iwamoto N. 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